Alzheimer’s disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission.
Objective:
We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients.
Methods:
We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC).
Results:
Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC.
Conclusions:
CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.
StintonC, McKeithI, TaylorJP, LafortuneL, MioshiE, MakE, CambridgeV, MasonJ, ThomasA, O’BrienJT (2015) Pharmacological management of Lewy body dementia: A systematic review and meta-analysis. Am J Psychiatry172, 731–742.
3.
TaylorJ-P, McKeithIG, BurnDJ, BoeveBF, WeintraubD, BamfordC, AllanLM, ThomasAJ, O’BrienJT (2020) New evidence on the management of Lewy body dementia. Lancet Neurol19, 157–169.
4.
LongJM, HoltzmanDM (2019) Alzheimer disease: An update on pathobiology and treatment strategies. Cell179, 312–339.
5.
ClarkeJR, RibeiroFC, FrozzaRL, De FeliceFG, LourencoMV (2018) Metabolic defects in Alzheimer’s disease: From basic neurobiology to clinical approaches. J Alzheimers Dis64, 405–426.
De FeliceFG, LourencoMV (2015) Brain metabolic stress and neuroinflammation at the basis of cognitive impairment in Alzheimer’s disease. Front Aging Neurosci7, 94.
VosselKA, BeagleAJ, RabinoviciGD, ShuH, LeeSE, NaasanG, HegdeM, CornesSB, HenryML, NelsonAB, SeeleyWW, GeschwindMD, Gorno-TempiniML, ShihT, KirschHE, GarciaPA, MillerBL, MuckeL (2013) Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol70, 1158–1166.
17.
SurendranathanA, SuL, MakE, PassamontiL, HongYT, ArnoldR, Vazquez RodriguezP, Bevan-JonesWR, BrainSAE, FryerTD, AigbirhioFI, RoweJB, O’BrienJT (2018) Early microglial activation and peripheral inflammation in dementia with Lewy bodies. Brain141, 3415–3427.
18.
GilmanS, KoeppeRA, LittleR, AnH, JunckL, GiordaniB, PersadC, HeumannM, WernetteK (2004) Striatal monoamine terminals in Lewy body dementia and Alzheimer’s disease. Ann Neurol55, 774–780.
19.
Abu-RumeilehS, SteinackerP, PolischiB, MammanaA, Bartoletti-StellaA, OecklP, BaiardiS, ZenesiniC, HussA, CortelliP, CapellariS, OttoM, ParchiP (2019) CSF biomarkers of neuroinflammation in distinct forms and subtypes of neurodegenerative dementia. Alzheimers Res Ther12, 2.
20.
DrummondC, CoutinhoG, MonteiroMC, AssuncaoN, TeldeschiA, SouzaAS, OliveiraN, BramatiI, SudoFK, VanderborghtB, BrandaoCO, FonsecaRP, Oliveira-SouzaR, MollJ, MattosP, Tovar-MollF (2019) Narrative impairment, white matter damage and CSF biomarkers in the Alzheimer’s disease spectrum. Aging11, 9188–9208.
21.
LourencoMV, RibeiroFC, SudoFK, DrummondC, AssuncaoN, VanderborghtB, Tovar-MollF, MattosP, De FeliceFG, FerreiraST (2020) Cerebrospinal fluid irisin correlates with amyloid-beta, BDNF, and cognition in Alzheimer’s disease. Alzheimers Dement (Amst)12, e12034.
22.
LourencoMV, FrozzaRL, de FreitasGB, ZhangH, KincheskiGC, RibeiroFC, GoncalvesRA, ClarkeJR, BeckmanD, StaniszewskiA, BermanH, GuerraLA, Forny-GermanoL, MeierS, WilcockDM, de SouzaJM, Alves-LeonS, PradoVF, PradoMAM, AbisambraJF, Tovar-MollF, MattosP, ArancioO, FerreiraST, De FeliceFG (2019) Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med25, 165–175.
23.
BeckmanD, SantosLE, AmericoTA, LedoJH, de MelloFG, LindenR (2015) Prion protein modulates monoaminergic systems and depressive-like behavior in mice. J Biol Chem290, 20488–20498.
24.
Monge-AcunaAA, Fornaguera-TriasJ (2009) A high performance liquid chromatography method with electrochemical detection of gamma-aminobutyric acid, glutamate and glutamine in rat brain homogenates. J Neurosci Methods183, 176–181.
25.
SellesMC, OliveiraMM, FerreiraST (2018) Brain inflammation connects cognitive and non-cognitive symptoms in Alzheimer’s disease. J Alzheimers Dis64, S313–S327.
26.
FerreiraST, LourencoMV, OliveiraMM, De FeliceFG (2015) Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer’s disease. Front Cell Neurosci9, 191.
27.
Paula-LimaAC, Brito-MoreiraJ, FerreiraST (2013) Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer’s disease. J Neurochem126, 191–202.
GateD, SaligramaN, LeventhalO, YangAC, UngerMS, MiddeldorpJ, ChenK, LehallierB, ChannappaD, De Los SantosMB, McBrideA, PluvinageJ, ElahiF, TamGK, KimY, GreiciusM, WagnerAD, AignerL, GalaskoDR, DavisMM, Wyss-CorayT (2020) Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature577, 399–404.
34.
PilletLE, TaccolaC, CotoniJ, ThiriezH, AndreK, VerpillotR (2020) Correlation between cognition and plasma noradrenaline level in Alzheimer’s disease: A potential new blood marker of disease evolution. Transl Psychiatry10, 213.
35.
EhrenbergAJ, NguyAK, TheofilasP, DunlopS, SuemotoCK, Di Lorenzo AlhoAT, LeiteRP, Diehl RodriguezR, MejiaMB, RubU, FarfelJM, de Lucena Ferretti-RebustiniRE, NascimentoCF, NitriniR, PasquallucciCA, Jacob-FilhoW, MillerB, SeeleyWW, HeinsenH, GrinbergLT (2017) Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: The pathological building blocks of early Alzheimer’s disease. Neuropathol Appl Neurobiol43, 393–408.
36.
KangSS, LiuX, AhnEH, XiangJ, ManfredssonFP, YangX, LuoHR, LilesLC, WeinshenkerD, YeK (2020) Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus. J Clin Invest130, 422–437.
37.
AdolfssonR, GottfriesCG, RoosBE, WinbladB (1979) Changes in the brain catecholamines in patients with dementia of Alzheimer type. Br J Psychiatry135, 216–223.
38.
PamphlettR, Kum JewS (2015) Different populations of human locus ceruleus neurons contain heavy metals or hyperphosphorylated tau: Implications for amyloid-beta and tau pathology in Alzheimer’s disease. J Alzheimers Dis45, 437–447.
39.
MorimotoS, TakaoM, HatsutaH, NishinaY, KomiyaT, SengokuR, NakanoY, UchinoA, SumikuraH, SaitoY, KanemaruK, MurayamaS (2017) Homovanillic acid and 5-hydroxyindole acetic acid as biomarkers for dementia with Lewy bodies and coincident Alzheimer’s disease: An autopsy-confirmed study. PLoS One12, e0171524.
40.
AertsMB, EsselinkRA, ClaassenJA, AbdoWF, BloemBR, VerbeekMM (2011) CSF tau, Abeta42, and MHPG differentiate dementia with Lewy bodies from Alzheimer’s disease. J Alzheimers Dis27, 377–384.
41.
KanemaruK, YamanouchiH (2002) Assessment of CSF homovanillic acid levels distinguishes dementia with Lewy bodies from Alzheimer’s disease. J Neurol249, 1125–1126.
42.
BlennowK, WallinA, GottfriesCG, LekmanA, KarlssonI, SkoogI, SvennerholmL (1991) Significance of decreased lumbar CSF Levels of HVA and 5-HIAA in Alzheimer’s disease. Neurobiol Aging13, 107–113.
43.
SjögrenM, MinthonL, PassantU, BlennowK, WallinA (1998) Decreased monoamine metabolites in frontotemporal dementia and Alzheimer’s disease. Neurobiol Aging19, 379–384.
44.
MinersS, MouldingH, de SilvaR, LoveS (2014) Reduced vascular endothelial growth factor and capillary density in the occipital cortex in dementia with Lewy bodies. Brain Pathol24, 334–343.
